SONU20176289, a compound combining partial dopamine D(2) receptor agonism with specific serotonin reuptake inhibitor activity, affects neuroplasticity in an animal model for depression.

We investigated the efficacy of SONU20176289, a member of a group of novel phenylpiperazine derivatives with a mixed dopamine D(2) receptor partial agonist and specific serotonin reuptake inhibitor (SSRI) activity, in a chronic stress model of depression in male tree shrews. Animals were subjected to a 7-day period of psychosocial stress before treatment for 28 days with SONU20176289 (6 mg/kg/day, p.o.), during which stress was maintained. Stress reduced the in vivo brain concentrations of N-acetyl-aspartate, total creatine, and choline-containing compounds, as measured by localized proton magnetic resonance spectroscopy. Post mortem analyses revealed a reduced adult dentate cell proliferation and a decreased GluR2 expression in the prefrontal cortex. All these alterations were prevented by concomitant administration of SONU20176289. The results provide further support to the concept that antidepressant treatments may act by normalizing disturbed neuroplasticity, and indicate that combining dopamine D(2) receptor agonism with SSRI activity may serve as an effective tool in the treatment of depressive/anxiety syndromes.

Functional role of alpha1-adrenoceptors in the locus coeruleus: a microdialysis study.

The present study elucidates the role of alpha(1)-adrenoreceptors in the locus coeruleus (LC) using a dual-probe microdialysis in conscious rats. One probe sampled noradrenaline in the LC, whereas the second probe sampled noradrenaline in a main projection area, the prefrontal cortex (PFC). To investigate a possible tonic activation of LC neurons by alpha(1)-adrenoceptor, the alpha(1)-antagonist prazosin (10 microM) was infused into the LC. Extracellular noradrenaline in the LC decreased to about 50% of basal levels but no change of noradrenaline release was detected in the ipsilateral PFC. Next, the interaction between alpha(1)- and alpha(2)-adrenoceptors was investigated. Local administration of the alpha(2)-adrenoceptor antagonist idazoxan (100 microM) into the LC increased the noradrenaline release in the LC to about 400%, whereas noradrenaline release in the PFC rose to 150% of basal levels. A similar effect was seen when the specific alpha(2A)-adrenoceptor antagonist BRL 44408 (10 microM) was infused: extracellular noradrenaline in the LC and PFC increased to about 400 and 120% of the basal levels, respectively. When infusions of idazoxan (100 microM) or BRL 44408 (10 microM) into the LC were combined with prazosin (10 microM), the excitatory effects of the alpha(2)-adrenoceptor antagonists on the release of noradrenaline were strongly suppressed in the LC as well as in the ipsilateral PFC. It is concluded that alpha(1)-adrenoreceptors are involved in the regulation of LC activity. Apparently, alpha(1)- and alpha(2)-adrenoceptors have opposite roles in their function as autoreceptors on LC cells.

Examining SLV-323, a novel NK1 receptor antagonist, in a chronic psychosocial stress model for depression.

RATIONALE: Substance P antagonists have been proposed as candidates for a new class of antidepressant compounds. OBJECTIVES: We examined the effects of SLV-323, a novel neurokinin 1 receptor (NK1R) antagonist, in the chronic psychosocial stress paradigm of adult male tree shrews. METHODS: Animals were subjected to a 7 day period of psychosocial stress before being treated daily with SLV-323 (20 mg kg(-1) day(-1)). The psychosocial stress continued throughout the treatment period of 28 days. Brain metabolite concentrations were determined in vivo by proton magnetic resonance spectroscopy. Norepinephrine excretion was monitored from daily urine samples, and serum testosterone concentrations were measured at the end of the experiment. All animals were videotaped daily to analyze scent-marking behavior and locomotor activity. Cell proliferation in the dentate gyrus and hippocampal volume were measured postmortem. RESULTS: Stress significantly decreased cerebral concentrations of N-acetyl-aspartate, total creatine, and choline-containing compounds in vivo and resulted in an increase of urinary norepinephrine and decrease of serum testosterone concentrations. Moreover, stressed animals displayed decreased scent-marking behavior and locomotor activity. The proliferation rate of the granule precursor cells in the dentate gyrus was reduced, and hippocampal volume was mildly decreased. The stress-induced alterations in the central nervous system were partially prevented by concomitant administration of SLV-323, while drug treatment had only a minor effect on the stress-induced behavioral changes. CONCLUSIONS: The novel NK1R antagonist SLV-323 has certain antidepressant-like effects in a valid animal model of depression.

Regulation of the release of serotonin in the dorsal raphe nucleus by alpha1 and alpha2 adrenoceptors.

To investigate the modulation of serotonin release in the dorsal raphe nucleus (DRN) by alpha(1) and alpha(2) adrenoceptors, dual-probe microdialysis was performed in conscious rats. The specific alpha(1) and alpha(2) adrenoceptor agonists and antagonists were locally infused into the DRN via retrograde microdialysis. The release of serotonin was simultaneously sampled from the DRN and prefrontal cortex (PFC). Infusion of the alpha(1) adrenoceptor agonist cirazoline into the DRN (100 microM) produced an increase in the release of serotonin in the DRN to 200% of the basal levels, but no effect was seen in the PFC. After infusion of the alpha(1) adrenoceptor antagonist prazosin into the DRN (100 microM) the release of serotonin decreased in the DRN and PFC to about 40% and 65% of the basal levels, respectively. Infusion of the alpha(2) adrenoceptor agonist clonidine into the DRN (100 microM) slightly but significantly decreased the level of serotonin in the DRN as well as in the PFC to about 70% of the basal levels. Infusion of the alpha(2A) adrenoceptor antagonist BRL 44408 into the DRN (100 microM) caused an increase of serotonin release in the DRN to 270% of the basal levels, but at the same time no changes were seen in the extracellular levels of serotonin in the PFC. The present study demonstrates that alpha(1) as well as alpha(2) adrenoceptors in the DRN modulate the release of serotonin in the DRN, and that alpha(1) adrenoceptors in the DRN are maximally stimulated during resting conditions.

The interaction between the locus coeruleus and dorsal raphe nucleus studied with dual-probe microdialysis.

The interaction between the locus coeruleus and dorsal raphe nucleus was investigated by means of dual-probe microdialysis in conscious rats. The release of noradrenaline and 5-hydroxytryptamine (5-HT) after inhibition or stimulation of locus coeruleus and dorsal raphe activity was sampled in both nuclei and analysed by high-pressure liquid chromatography (HPLC). The inhibition of locus coeruleus activity by the infusion of the alpha(2)-adrenoceptor agonist clonidine (100 microM) decreased the release of noradrenaline to 20% in the locus coeruleus and 30% in the dorsal raphe, whilst the release of 5-HT decreased to 80% of control in the two brain areas. The excitation of locus coeruleus activity by the muscarinic receptor agonist carbachol (100 microM) led to an increase in the release of noradrenaline to 240% and 220% of control in the locus coeruleus and dorsal raphe, respectively. The release of 5-HT in both nuclei did not respond to the carbachol infusion into the locus coeruleus. Infusion of the 5-HT(1A) receptor agonist flesinoxan into the dorsal raphe (1 microM) significantly decreased the release of 5-HT in the dorsal raphe and locus coeruleus to 45% and 65% of control, respectively. The release of noradrenaline was decreased in the dorsal raphe to 45% by flesinoxan, whereas no changes were seen in the release of noradrenaline in the locus coeruleus. In conclusion, the innervation of the dorsal raphe by the locus coeruleus has a slight excitatory effect on the release of 5-HT in the dorsal raphe. The dorsal raphe does not exert a direct inhibitory influence on the release of noradrenaline in the locus coeruleus. Finally, the release of noradrenaline in the dorsal raphe may be locally regulated by 5-HT(1A) receptors.